DESCRIPTION: (adapted from the abstract) The mechanisms responsible for the hypertrophy that accompanies hypertension are unclear. The principal investigator's (PI's) recent observations suggest that superoxide anion may serve as a hypertrophic signal in cultured vascular smooth muscle cells. In many other systems, most notably tumor cells, oxygen-derived free radicals stimulate growth, implying that the redox state of the cell may be a common step at which growth control can be achieved. Therefore, the proteins and enzymes that produce reactive oxygen species or serve as the antioxidant defense system are critical determinants of the course of vascular disease. In cultured vascular smooth muscle cells, the PI has shown that vasoactive agents such as angiotensin II cause a delayed generation of superoxide anion by activating an NADPH/NADH oxidase located at the plasma membrane. The pathways leading to oxidase activation, and the pathways linking oxidase activation to hypertrophy will be examined in this study. In the first Specific Aim, the PI will determine the biochemical pathways responsible for the activation of the NADPH/NADH oxidase. In Specific Aim 2, she will look at expression of cytochrome b558, the electron transfer component of the oxidase, using molecular biologic techniques. The relationship of this cytochrome to vascular smooth muscle superoxide anion production and hypertrophy will be examined in Specific Aim 3. Finally, in Specific Aim 4, she will measure expression of cytochrome b558 in two animal models of hypertension. These studies will provide insight into the mechanisms responsible for vascular hypertrophy in hypertension. The PI hypothesizes that the modification of NADPH/NADH oxidase activity and therefore the oxidative state of the smooth muscle cells may be central to controlling the expression of a subset of genes involved in the development of hypertension. Understanding the cellular events involved in controlling the oxidative environment of VSMC may thus lead to the development of specific therapeutic strategies.